Heart failure (HF) is a major global public health problem, with a prevalence of 64.3 million cases worldwide (1). HF is the leading cause of hospitalization among older patients and is associated with high mortality (2, 3). High blood pressure (BP) is a modifiable risk factor for incident HF, and clinical trials have demonstrated that lowering BP can substantially decrease the risk of developing HF (4–6). For patients with established HF, the latest American College of Cardiology/American Heart Association guidelines for HF and hypertension recommend that the optimal systolic blood pressure (SBP) in those with hypertension should be <130 mmHg; however, this recommendation is extrapolated from populations without HF (7, 8).

Among patients hospitalized for HF, previous studies have shown that those with lower admission SBP were at a higher risk of clinical outcomes (9–12); while the association between SBP during hospitalization and long-term clinical outcomes remains unclear (12–17). Some studies demonstrated that a low SBP level may have a paradoxical association with an increased risk of death (12, 13), and one study reported that a relatively normal SBP may also be associated with unfavorable outcomes (14); while others found a J-curve association between SBP and outcomes (16, 17). Although the prevalence of HF readmission is high, there is still a lack of knowledge about the association of SBP during hospitalization with long-term HF readmission after the index hospitalization and whether the association is causal or due to reverse causality (13, 14). Patients with HF represent a heterogeneous population and the association between SBP and clinical outcomes could be different among subgroups of clinical importance, such as the subgroups of left ventricular ejection fraction (LVEF), age, comorbidities, and medications (13, 18–20), which requires further investigation to help explore the causality.

Accordingly, this study aimed to investigate the association of SBP in a stable phase during hospitalization with 1-year clinical outcomes in the overall population and in clinically important subgroups based on a prospective multicenter cohort with a large number of patients hospitalized for HF, which could provide more evidence for future recommendations on BP management, and help physicians optimize BP management strategies to improve outcomes of patients with HF.

Findings from this study demonstrate that lower SBP in a stable phase during hospitalization was associated with an increased risk of 1-year death in patients hospitalized for HF, and our study for the first time observed a J-curve association between SBP in a stable phase during hospitalization and 1-year HF readmission. The associations remained consistent in various clinically important subgroups, including the subgroups of age, sex, LVEF, HF type, hypertension, and coronary heart disease; the consistency was not affected when using important medications for HF with BP-lowering effects.

Our study expands the literature by providing an insight into the association of SBP and death among a whole spectrum of HF with more accurate BP measurement. In our study, we measured BP in a stable phase during hospitalization before discharge according to the standard approach; i.e., using the unified BP monitor and measuring BP at least twice to get the average. This approach maximumly reduced the measurement bias, and we could therefore obtain more accurate SBP values than previous studies which only collected SBP values from routine clinical measurement at discharge (12–16). Our study demonstrated patients with SBP < 110 mmHg had a 1.7-fold higher risk of death than those with SBP of 130–139 mmHg. Similar to our findings, several other studies found an inverse association of SBP at discharge with the risk of death in patients hospitalized for HF (12–14, 20). However, these studies only included patients with HFrEF or HFpEF (12–14, 20), while patients with HFmrEF were usually overlooked and less well-studied. In our study, all three types of patients were included and we did not observe heterogeneity in the associations between SBP and death across LVEF levels. In the sensitivity analysis, we excluded the patients with SBP < 90 mmHg, who were more likely to have worse clinical status and greater adverse outcomes (25), and the association remained consistent. Accordingly, our findings suggest that clinicians should be cautious about the lowering of SBP to a low level during hospitalization for patients with HF.

Our data suggest that the association between SBP < 110 mmHg and increased risk may be causal rather than due to reverse causality. It is possible that patients with lower SBP had more progressive systolic dysfunction and the resultant neurohormonal activation may result in a higher risk of death (26); however, the effects of SBP on death were homogeneous in patients with HF with different LVEF levels. In addition, lower BP might cause coronary hypoperfusion and result in increased deaths among patients with the compromised coronary flow (27, 28); nevertheless, the associations were consistent in patients with and without coronary heart disease. Another possible explanation could be related to the treatment patterns. Because patients with lower SBP tended to be undertreated with HF therapy, prior studies left open the possibility that suboptimal treatment could contribute to the poor outcomes of these patients (29); however, in this study, among patients with SBP <110 mmHg, most of them have been treated with proved medications during hospitalization and at discharge. The use of β-blockers and aldosterone antagonists during hospitalization and at discharge was even higher in patients with SBP <110 mmHg than other SBP groups. Besides, the association between SBP and death was significant no matter whether patients received these medications or not. Moreover, we excluded the patients who died within 30 days after discharge because of their greater burden of comorbidities and higher illness severities, and the results remained the same (30). Thus, this study indicates that lower SBP may not be a marker of more advanced disease or worse health status, which suggests that SBP per se may be directly associated with the increased risks. And the randomized clinical trials to evaluate the optimal SBP goals in HF patients are warranted.

This study is the first to reveal a J-curve association between SBP in a stable phase during hospitalization and 1-year HF readmission in patients hospitalized for HF with the nadir SBP around 130 mmHg. Some previous studies have examined the association between discharge SBP and HF readmission, but they did not evaluate whether the non-linear association existed (14, 20). The association between SBP and HF readmission in this study agreed with the results from a previous analysis by Lee et al. which described a non-linear association between on-treatment SBP and long-term HF readmission in a Korean acute heart failure cohort, with the lowest risk at an SBP of 144 mmHg (19). In our study, among patients with SBP ≥ 130 mmHg, more than three quarters had a medical history of hypertension; and in those with SBP ≥ 150 mmHg, more than 90% had hypertension. Persistent high SBP could increase the left ventricular afterload and peripheral vascular resistance, leading to a high possibility of the clinical deterioration (31). As a result, it is possible that HF patients with higher SBP are more likely to have readmission due to HF aggravation (19). More investigations are needed to confirm the findings and further elucidate the underlying mechanism.

This study should be considered in the context of limitations. Although we performed multivariable analyses accounting for extensive baseline characteristics, unmeasured and residual confounders could exist, which is inevitable for the observational studies. We had limited data on post-discharge SBP, and SBP crossover during follow-up may attenuate between-group differences in the outcomes. As this study was based on patients hospitalized for HF, the results could not be generalizable to other HF populations, especially ambulatory HF patients, because the clinical characteristics of patients in these two settings are different.

In conclusion, among patients hospitalized for HF, lower SBP in a stable phase during hospitalization portends an increased risk of 1-year death, and a J-curve association has been observed between SBP and 1-year HF readmission with the nadir SBP around 130 mmHg. The associations remained consistent across various subgroups of clinical importance. Our observation could provide more evidence for future recommendations on BP management among patients with HF.

The datasets presented in this article are not readily available because, the China PEACE 5p-HF Study is a national program, and as the government policy stipulates, it is not permissible for the researchers to make the raw data publicly available at this time. Requests to access the datasets should be directed to JLi, jing.li@fwoxford.org.

The studies involving human participants were reviewed and approved by the Central Ethics Committee at Fuwai Hospital and Local Internal Ethics Committees at Study Hospitals. The patients/participants provided their written informed consent to participate in this study.

JLi, JLiu, and XH designed the study. XH, XB, and SH designed the statistical methods and analyzed the data. XH drafted the manuscript. LZ, BW, FM, AT, TY, and YL revised the manuscript for important intellectual content. All the authors participated in the interpretation of the data and approved the final version of the manuscript.

This work was supported by the National Key Research and Development Program (2018YFC1312400, 2018YFC1312401, and 2018YFC1312404) from the Ministry of Science and Technology of China, the CAMS Innovation Fund for Medical Science (2021-1-I2M-009), and the National Key Technology R&D Program (2015BAI12B02) from the Ministry of Science and Technology of China.

JLi reported receiving research grants, through Fuwai Hospital, from the Chinese government and Chinese Academy of Medical Sciences for work to improve the management of hypertension and blood lipids and to improve patient outcomes of cardiovascular disease and COVID-19; receiving research agreements, through the National Center for Cardiovascular Diseases and Fuwai Hospital, from Amgen for a multicenter clinical trial assessing the efficacy and safety of omecamtiv mecarbil and for dyslipidemic patient registration; receiving a research agreement, through the Fuwai Hospital, from Sanofi for a multicenter clinical trial on the effects of sotagliflozin; receiving a research agreement, through the Fuwai Hospital, with the University of Oxford for a multicenter clinical trial of empagliflozin; receiving a research agreement, through the National Center for Cardiovascular Diseases, from AstraZeneca for clinical research methods training outside the submitted work; and receiving a research agreement, through the National Center for Cardiovascular Diseases, from Lilly for physician training outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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